Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the third leading cause of all cancer-related deaths in the world (Ferlay, J., et al., Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International journal of cancer, 2010. 127(12): p. 2893-2917). More than 600,000 deaths are reported globally each year. HCC affects all segments of the world population (El-Serag, H. B. and K. L. Rudolph, Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology, 2007. 132(7): p. 2557-2576). Approximately 75% of HCC patients are concentrated in Asia, but a recent trend of rising rates of HCC has been reported in several developed countries including Europe and the United States (Venook, A. P., et al., The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. The Oncologist, 2010. 15 (Supplement 4): p. 5-13).
The current standard of care can be classified into 3 broad categories including (1) surgical treatment; (2) local ablation therapy; and (3) chemotherapy. Surgical treatments include hepatic resection and liver transplantation. Non-surgical treatments include local ablation therapies, of which percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) are most commonly practiced; and chemotherapy which is either administered via transarterial chemoembolization (TACE) or systemically. Standard treatments involve high costs. For example, molecular targeted therapy using sorafenib as recommended by NCCN/AASLD/JSH/ESMO Guideline is expensive, with an average cost around US$6,000 per month.
Oral consumption of viable probiotics is one of the many alternative experimental cancer treatments that have been reported in the literature. Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. Efficacy of probiotics on cancer development is suggested by several lines of scientific evidence and hypotheses, including the increase in immune cell activation, increase of the antitumor surveillance immune activity, promotion of anti-inflammation, and the suppression of bacteria converting procarcinogens (de LeBlanc, A. d. M., C. Matar, and G. Perdigón, The application of probiotics in cancer. British Journal of Nutrition, 2007. 98(S1): p. 5105-5110). Most data were obtained from cases of colon and breast carcinomas. In the former, prevention was first achieved in animal models and was ascribed to the significant anti-inflammatory effect of probiotics (Perdigon, G., et al., Role of yoghurt in the prevention of colon cancer. European journal of clinical nutrition, 2002. 56: p. S65). While in the case of breast cancer, suggested beneficial effects of probiotics appear to be mediated by an increase of the antitumor surveillance immune activity (de Moreno de LeBlanc, A., et al., Effects of milk fermented by Lactobacillus helveticus R389 on immune cells associated to mammary glands in normal and a breast cancer model. Immunobiology, 2005. 210(5): p. 349-358).
In the context of liver cancer, there are reports regarding the use of probiotic supplement (viable Lactobacillus rhamnosus LC705 and Propionibacterium freudenreichii subsp. Shermani) as a dietary approach to decrease the risk of liver cancer. The proposed mechanism is related to blocking intestinal absorption of carcinogen aflatoxin B1 by binding to the aflotoxin, and thereby reducing the biologically effective dose of dietary aflatoxin exposure (El-Nezami, H. S., et al., Probiotic supplementation reduces a biomarker for increased risk of liver cancer in young men from Southern China. The American journal of clinical nutrition, 2006. 83(5): p. 1199-1203).
There is substantial evidence that some probiotics can provide benefits by modulating immune functions, including modulating T helper cell response. Depending on the disease model, these probiotics may induce T-cell hyporesponsiveness (Braat, H., et al., Lactobacillus rhamnosus induces peripheral hyporesponsiveness in stimulated CD4+ T cells via modulation of dendritic cell function. The American journal of clinical nutrition, 2004. 80(6): p. 1618-1625), up-regulating or down-regulating production of cytokines relating to Th1/Th2 response (Valio Ltd, R.D.a.S., LGG® Summatim, in Health effects of LGG2009; Mutaflor. Most Recent Mutaflor Evidence and Clinical Studies (2006-2010). 2010; Available on webpagemutaflor.ca/health-care-professionals/mutaflor-clinical-studies/; Sigma-Tau Pharmaceuticals, I. VSL#3® references. 2012; Available on webpage vsl3.com/hcp/references.asp). Escherichia coli Nissle 1917 (EcN) has been clinically studied for use in ulcerative colitis, Crohn's Disease, chronic constipation, prolonged diarrhea, irritable bowel syndrome and pouchitis (Mutaflor. Most Recent Mutaflor Evidence and Clinical Studies (2006-2010). 2010; Available on webpagemutaflor.ca/health-care-professionals/mutaflor-clinical-studies/). Lactobacillus acidophilus (Moro) Hansen and Mocquot strain GG (ATCC 53103) (LGG) has been shown to enhance antibody formation during viral infection and respiratory infections, in addition to treating the above gastrointestinal disorder (Valio Ltd, R.D.a.S., LGG® Summatim, in Health effects of LGG2009). VSL#3® (Sigma-Tau) is also widely used in clinical management of ulcerative colitis, irritable bowel syndrome, and ileal pouch (Sigma-Tau Pharmaceuticals, I. VSL#3® references. 2012; Available on webpage vsl3.com/hcp/references.asp). In animal models, VSL#3® has shown protective efficacy in delaying transition to dysplasia in colitis-associated colorectal by attenuating various inflammatory-associated parameters (Appleyard, C. B., et al., Pretreatment with the probiotic VSL#3 delays transition from inflammation to dysplasia in a rat model of colitis-associated cancer. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2011. 301(6): p. G1004-G1013).
Apart from viable probiotics, health benefits of heat-inactivated probiotics supplementation have also been studied, although the disease model is not cancer. Probiotic strains such as L. acidophilus L-92, L. brevis SBC8803, L. casei Shirota, L. gasseri OLL2809, L. paracasei KW3110, L. pentosus S-PT84 still show immunomodulatory functions, including affecting IgE production, and affecting Th1/Th2 cytokine production even after heat treatment in animal models of sensitization and allergic manifestations (Sashihara, T., N. Sueki, and S. Ikegami, An analysis of the effectiveness of heat-killed lactic acid bacteria in alleviating allergic diseases. Journal of dairy science, 2006. 89(8): p. 2846-2855). Meanwhile, non-probiotic bacteria have been heat-attenuated and used in cancer studies in the form of cancer vaccines. Examples of this include Coley's toxins, a mixture of heat-killed S. pyogenes and S. marcescens, where attenuated bacteria have been administered systemically to induce severe inflammatory reaction against tumor by bacteria's endotoxin and induce apoptosis. Though it is mainly used in the treatment of sarcomas, lymphomas and melanomas (Cann, S. H., J. Van Netten, and C. Van Netten, Dr William Coley and tumour regression: a place in history or in the future. Postgraduate medical journal, 2003. 79(938): p. 672-680), its use in HCC patients has been reported in one study as an adjuvant treatment. However, this kind of treatment could be followed by severe fever with high risk of patient's death (Richardson, M. A., et al., Coley toxins immunotherapy: a retrospective review. Alternative therapies in health and medicine, 1999. 5(3): p. 42).